The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (American Journal of Medicine 1976, 60, 80) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglycemia. The diabetic groups in these studies included both insulin dependent (IDDM) and noninsulin dependent (NMDDM) subjects.
Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
The association of hyperinsulinemia with obesity and with ischemic diseases, of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease.
Since most of these studies actually excluded diabetic subjects, data relating the risk of atherosclerotic diseases to the diabetic condition are not as numerous, but point in the same direction as for nondiabetic subjects (Pyorala et al). However, the incidence of atherosclerotic diseases in morbidity and mortality statistics in the diabetic population exceeds that of the nondiabetic population (Pyorala et al; Jarrett Diabetes/Metabolism Reviews 1989, 5, 547; Harris et al, Mortality from diabetes, in Diabetes in America 1985).
The independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin/glucose clamps, tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose), strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins. The interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase. PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. The enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity, include PTP1B, LAR, PTPa and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).
McGuire et al. (Diabetes 1991, 40, 939), demonstrated that nondiabetic glucose intolerant subjects possessed significantly elevated levels of PTPase activity in muscle tissue vs. normal subjects, and that insulin infusion failed to suppress PTPase activity as it did in insulin sensitive subjects.
Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observed significantly increased PTPase activity in the livers of two rodent models of IDDM, the genetically diabetic BB rat, and the STZ-induced diabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic ob/ob mice, a genetic rodent model of NIDDM.
The compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase-1B (hPTP-1B) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
P. N. Devine et al (WO 97/21693; Jun. 19, 1997) disclosed examples D under a method of preparation (B, D (independently=halogen, phenyl, alkyl; X=alkyl, aryl; Y=(CH2)0-3CH3, Ph, NH(CH2)0-3CH3, N((CH2)0-3CH3)2, NH2, NO2, NHCO(CH2)0-3CH3, NHCO2(CH2)0-3CH3, CH2O(CH2)0-3CH3, OPh; O(CH2)1-4O(CH2)0-5CH3, O(CH2)1-4OPh, OCO2(CH2)0-5CH3, CON((CH2)0-5CH3)2, O(CH2)1-4O(CH2)1-6Ph). The synthetic process to prepare the compounds represented by compounds D was different to the processes used to prepare the 2,3,5-substituted biphenyls of this invention. 
G. Cain and C. J. Eyermann (U.S. Pat. No. 5,523,302; Jun. 4, 1996) disclosed examples A (B, D (independently=cycloalkyl, alkyl, aralkyl) as agents which inhibit platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders. The synthetic process to prepare the compounds represented by compounds A was different to the processes used to prepare the 2,3,5-substituted biphenyls of this invention. 
M. Wayne et al (WO 94/22835, WO 94/22834; Oct. 13, 1994) disclosed examples B (B, D (independently=alkyl, halogen) as agents which inhibit platelet aggregation, as thrombolytics and/or for the treatment of thromboembolic disorders. The synthetic process to prepare the compounds represented by compounds B was different to the processes used to prepare the 2,3,5-substituted biphenyls of this invention 
S. W. Bagley et al (U.S. Pat. No. 5,334,598; Aug. 2, 1994) disclosed examples C (B, D (independently=phenyl, naphthyl, alkyl, halogen) as agents which have endothelin antagonist activity and are therefore useful in treating cardiovascular disorders. Our present invention does not claim a compound of this genus, namely 2-phenyl-2-phenoxy acetic acids. The synthetic process to prepare the compounds represented by compounds C was different to the processes used to prepare the 2,3,5-substituted biphenyls of this invention. A similar set of compounds is disclosed in C. M. Harvey et al (WO 96/09818; Apr. 4, 1996), W. J. Greenlee et al (WO 91/11909; Aug. 22, 1991), and W. J. Greenlee et at (WO 91/12002; Aug. 22, 1991). A similar set of arguments apply. 
This invention provides a compound of formula I having the structure 
wherein:
B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;
R1 is hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94SO2Ph(OH)(CO2H), xe2x80x94CH(R2)W, xe2x80x94CH2CH2Y, or xe2x80x94CH2CH2CH2Y;
R2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, xe2x80x94CH2(1H-imidazol-4-yl), xe2x80x94CH2(3-1H-indolyl), xe2x80x94CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), xe2x80x94CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or xe2x80x94CH2(3-pyridyl);
W is xe2x80x94CO2R3, xe2x80x94CONHOH, xe2x80x94CN, xe2x80x94CONHR3, aryl, heteroaryl, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR3, or xe2x80x94CHxe2x95x90NHNHR3;
Y is xe2x80x94W, xe2x80x94OCH2CO2R3, aryl, heteroaryl, xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94OR3, xe2x80x94O(Cxe2x95x90O)NR4R5, xe2x80x94NR3(Cxe2x95x90O)OR3, xe2x80x94NR3(Cxe2x95x90O)NR4R5, or xe2x80x94NR4R5;
R3 is hydrogen or alkyl of 1-6 carbon atoms;
R4 and R5 are each, independently, hydrogen, or alkyl of 1-6 carbon atoms or R4 and R5 are, together, xe2x80x94(CH2)nxe2x80x94, or xe2x80x94CH2CH2XCH2CH2xe2x80x94;
X is O, S, SO, SO2, NR3, or CH2;
n is 2 to 5;
C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, xe2x80x94CONR6R7, xe2x80x94NR3CONR6R7, xe2x80x94NR3COR6, xe2x80x94OR6, xe2x80x94O2CNR6R7, xe2x80x94NR3CO2R6, xe2x80x94O2CR6, xe2x80x94CH2OR6, xe2x80x94NR6R7, xe2x80x94CR3xe2x95x90CR3R8, xe2x80x94CPh3, xe2x80x94CH2NR6R7, or 
R6 and R7 are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, xe2x80x94(CH2CH2O)nCH3, xe2x80x94(CH2)mA or R6 and R7 are, together, xe2x80x94(CH2)pxe2x80x94, xe2x80x94(CH2)2N(CH3)(CH2)4xe2x80x94, xe2x80x94(CH2)2N(R8)(CH2)2xe2x80x94, or xe2x80x94(CH2)2CH(R8)xe2x80x94(CH2)2xe2x80x94;
R8 is hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, xe2x80x94(CH2CH2O)nCH3, xe2x80x94(CH2CH2CH2O)nCH3, or xe2x80x94(CH2)mA;
A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, xe2x80x94CHF2, xe2x80x94CH2F, xe2x80x94CF3, xe2x80x94(CH2CH2O)nCH3, xe2x80x94(CH2CH2CH2O)nCH3, xe2x80x94CO2R3, xe2x80x94O(Cxe2x95x90O)NR6R7, aralkyloxy, or heteroaralkyloxy;
m is 2 to 16
p is 2 to 12
or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. It is preferred that the aryl portion of the aryl, aralkyl, aryloxy, or aralkyloxy substituent is a phenyl or naphthyl; with phenyl being most preferred. The aryl moiety may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, xe2x80x94CO2H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms. The heteroaryl portion of the heteroaryl, heteroaralkyl, heteroaryloxy, or heteroaralkyloxy substituent may be pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, thiazolyl, oxazolyl, imidazolyl, oxadiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl. The heteroaryl moiety may be optionally mono-, di-, or tri-substituted in the case of pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, may be optionally mono- or di-substituted in the case of thiazolyl, oxazolyl, or imidazolyl, and may be optionally monosubstituted in the case of oxadiazolyl, tetrazolyl, or triazolyl, with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, xe2x80x94CO2H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
Preferred compounds are those in which B is aryl and D is either aryl or halogen. More preferred compounds of this invention are:
(3,3xe2x80x3-Dichloro-5xe2x80x2-dodecylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid;
(3-Bromo-3xe2x80x2-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy)acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid;
(5xe2x80x2-Octadecyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid;
(5xe2x80x2-dodecylcarbamoyl-3,3xe2x80x3-bis-trifluoromethyl-{1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid;
(3-bromo-5-dodecylcarbamoyl-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy)acetic acid;
(5xe2x80x2-(8-phenyloctylcarbamoyl-3,3xe2x80x3-bis-trifluoromethyl-{1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid;
(5xe2x80x2-Dodecylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Dodecylcarbamoyl-4,4xe2x80x3-dimethoxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(3-Chloro-5xe2x80x2-dodecylcarbamoyl-4xe2x80x3-methoxy-[1,1xe2x80x2;3xe2x80x2]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Dodecylcarbamoyl-3,3xe2x80x3-dimethoxy-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
[2-(3,3xe2x80x3-Dichloro-5xe2x80x2-dodecylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy-ethoxy]-acetic acid.
{5xe2x80x2-[6-(4-tert-Butyl-benzyloxy)-hexylcarbamoyl]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{5xe2x80x2-[6-(4-Benzyloxy-benzyloxy)-hexylcarbamoyl]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
[3xe2x80x3-Chloro-4-methoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
{3xe2x80x3-Chloro-4-methoxy-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
[3,3xe2x80x3-Dimethoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2-yloxy]-acetic acid
{2-[5xe2x80x2-(6-Phenyl-hexylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-ethoxy} acetic acid
{5xe2x80x2-[6-(2,4-Difluoro-benzyloxy)-hexylcarbamoyl]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2yloxy}-acetic acid
{5xe2x80x2-[6-(Biphenyl-4-ylmethoxy)-hexylcarbamoyl]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{3,3xe2x80x3-Dimethoxy-5xe2x80x3-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{2-[3,5,3xe2x80x3,5xe2x80x3-Tetrachloro-5xe2x80x2-[(6-phenyl-hexylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-ethoxy}-acetic acid
[4,4xe2x80x3-Dimethoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2.1xe2x80x3]terphenyl-2xe2x80x2yloxy]acetic acid sodium salt
(3,3xe2x80x3-Dichloro-5xe2x80x2-dodecylcarbamoyl-4,4xe2x80x3-difluoro[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl(-2xe2x80x2-yloxy)-acetic acid sodium salt
[3,3xe2x80x3-Dichloro-4-4xe2x80x3difluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)[-1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-(6-(2,5-dimethyl-furan-3-ylmethoxy)-hexylcarbamoyl]-4-4xe2x80x3-difluoro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
[3,5-Dichloro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
[5xe2x80x2-(8-Phenyl-octylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x3;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
4,4xe2x80x3-Difluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
{5xe2x80x2-[6-(2,5-Dimethyl-furan-3-ylmethoxy)-hexylcarbamoyl]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
(3-Bromo-5-dodecylcarbamoyl-4xe2x80x2-methoxy-biphenyl-2-yloxy)-acetic acid
[5xe2x80x2-(2-Hexadecylamino-3,4-dioxo-cyclobut-1-enylamino)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
(3,3xe2x80x3-Dichloro-5xe2x80x2-dodecylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(3-Bromo-3xe2x80x2-chloro-5-dodecylcarbamoyl-biphenyl-2-yloxy)-acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
(5xe2x80x2-Octadecyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Benzo[b]naphtho[2,3-d]thiophen-11-yl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Nitro-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Methoxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Bromo-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
[(5xe2x80x2-Phenyl[1,1xe2x80x2;3xe2x80x2,1xe2x80x3-terphenyl]-2xe2x80x2-yl)oxy]acetic acid
(1,3-Diphenyl-dibenzofuran-2-yloxy)-acetic acid
(2-Benzoyl-4,6-dibromo-benzofuran-5-yloxy)acetic acid
(5xe2x80x2-Butoxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Octyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(3,3xe2x80x3-Dichloro-5xe2x80x2-octyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(3,3xe2x80x3-Bis-acetylamino-5xe2x80x2-octyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Octyloxy-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(3,3xe2x80x3-Dinitro-5xe2x80x2-octyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(3,3xe2x80x3-Dimethoxy-5xe2x80x2-octyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(3-phenyl-propylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(2-pyridin-2-yl-ethylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[5xe2x80x2-(Benzyl-phenethyl-carbamoyl)-3,3xe2x80x3-Dichloro-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(4-phenyl-butylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[5-(Benzyl-phenethyl-carbamoyl)-3-bromo-3xe2x80x2-chloro-biphenyl-2-yloxy]acetic acid
[3-Bromo-3xe2x80x2-chloro-5-(2-pyridin-2-yl-ethylcarbamoyl)-biphenyl-2-yloxy]acetic acid
[5xe2x80x2-(Benzyl-phenethyl-carbamoyl)-3xe2x80x3-chloro-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3xe2x80x3-Chloro-5xe2x80x2-(2-pyridin-2-yl-ethylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3xe2x80x3-Chloro-5xe2x80x2-(3-phenyl-propylcarbamoyl]-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3xe2x80x3-Chloro-5xe2x80x2-(4-phenyl-butylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3xe2x80x3-Chloro-5xe2x80x2-(3-cyclopentyl-propylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3-Bromo-3xe2x80x2-chloro-5-(3-cyclopentyl-propylcarbamoyl)-biphenyl-2-yloxy]acetic acid
{5xe2x80x2-[2-(4-Bromo-phenyl)-ethylcarbamoyl]-3xe2x80x3-chloro-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(3-cyclopentyl-propylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[4xe2x80x3-Methoxy-5xe2x80x2-(2-pyridin-2-yl-ethylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[5xe2x80x2-(3-Cyclopentyl-propylcarbamoyl)-4xe2x80x3-methoxy-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[5xe2x80x2-(Benzyl-phenethyl-carbamoyl)-4xe2x80x3-methoxy-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[5xe2x80x2-(Benzyl-phenethyl-carbamoyl)-2-fluoro-4xe2x80x3-methoxy-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[5-(Benzylphenethyl-carbamoyl)-3-bromo-2xe2x80x2-fluoro-biphenyl-2-yloxy]acetic acid
[2-Fluoro-4xe2x80x3-methoxy-5xe2x80x2-(2-pyridin-2-yl-ethylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[2-Fluoro-4xe2x80x3-methoxy-5xe2x80x2-(3-phenyl-propylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3-Bromo-2xe2x80x2-fluoro-5-(2-pyridin-2-yl-ethylcarbamoyl)-biphenyl-2-yloxy]acetic acid
[3-Bromo-2xe2x80x2-fluoro-5-(3-phenyl-propylcarbamoyl)-biphenyl-2-yloxy]acetic acid
[5xe2x80x2-(3-Cyclopentyl-propylcarbamoyl)-2-fluoro-4xe2x80x3-methoxy-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3-Bromo-5-(3-cyclopentyl-propylcarbamoyl)-2xe2x80x2-fluoro-biphenyl-2-yloxy]acetic acid
[2-Fluoro-4xe2x80x3-methoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid [3-Bromo-2xe2x80x2-fluoro-5-(8-phenyl-octylcarbamoyl)-biphenyl-2-yioxy]acetic acid
[2-Fluoro-4xe2x80x3-methoxy-5xe2x80x2-(6-phenyl-hexylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy]acetic acid
[3-Bromo-2xe2x80x2-fluoro-5-(6-phenyl-hexylcarbamoyl)-biphenyl-2-yloxy]acetic acid [3,3xe2x80x3-Dichloro-5xe2x80x2-(6-phenyl-hexylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
{4xe2x80x3-Methoxy-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy} acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3,3xe2x80x3-Difluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
{3,3xe2x80x3-Difluoro-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-morpholin-4-yl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(2,6-dimethoxy-phenoxy)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy} acetic acid
{5xe2x80x2-[8-(Benzoxazol-2-ylsulfanyl)-octylcarbamoyl]-3,3xe2x80x3-dichloro-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-indol-1-yl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(3-cyano-phenoxy)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(4-chloro-benzyloxy)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(4-fluoro-3-methyl-phenoxy)-octylcarbamoyl]-[1,1 xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-imidazol-1-yl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[6-(naphthalen-1-ylcarbamoyloxy)-hexylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[6-(2,4-difluoro-phenylcarbamoyloxy)-hexylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[6-(4-phenoxy-phenylcarbamoyloxy)-hexylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(5-fluoro-indol-1-yl)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(5-methoxy-indol-1-yl)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(2,5-dimethyl-indol-1-yl)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(5-methoxy-2-methyl-indol-1-yl)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-2xe2x80x2-yloxy}acetic acid
(3 ,3xe2x80x3-Dichloro-5xe2x80x2-{[1-(4-phenyl-butoxymethyl)-cyclopropylmethyl]-carbamoyl}-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
[5xe2x80x2-(Benzofuran-2-carbonyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
3-[3xe2x80x3-(2-Carboxy-vinyl)-2xe2x80x2-methoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-3-yl]-acrylic acid
3-[3xe2x80x3-(2-Carboxy-ethyl)-2xe2x80x2-methoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x21xe2x80x3]-terphenyl-3-yl]-propionic acid
{5xe2x80x2-[(2-Butyl-benzofuran-3-ylmethyl)-amino]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-ylolxy}acetic acid methyl ester
{5xe2x80x2-[(2-Butyl-benzofuran-3-ylmethyl)-amino]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}acetic acid
{2,6-Dibromo-4-[(2-butyl-benzofuran-3-ylmethyl)-amino-phenoxy}acetic acid methyl ester
{2,6-Dibromo-4-[(2-butyl-benzofuran-3-ylmethyl)-arrino]-phenoxy}acetic acid
[2xe2x80x3-Fluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Dodecylcarbamoyl-2xe2x80x3-fluoro-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(5xe2x80x2-Dodecylcarbamoyl-2,2xe2x80x3-difluoro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
[2,2xe2x80x3-Difluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
[2,2xe2x80x3-Difluoro-5xe2x80x2-(6-phenyl-hexylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
{5xe2x80x2-[6-(2,4-Difluoro-phenoxy)-hexylcarbamoyl]-2,2xe2x80x3-difluoro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
(3xe2x80x3-Chloro-5xe2x80x2-dodecylcarbamoyl-2-fluoro-[1,1 xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
[3xe2x80x3-Chloro-2-fluoro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
{3-Chloro-5xe2x80x2-[6-(2,4-difluoro-phenoxy)-hexylcarbamoyl]-2xe2x80x3-fluoro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{3xe2x80x3-Chloro-2-fluoro-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{2,2xe2x80x3-Difluoro-5xe2x80x2-[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(4-chloro-benzenesulfinyl)-octylcarbamoyl]-[1, 1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(2,4-difluoro-phenoxy)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[12-(2,4-difluoro-phenoxy)-dodecylcarbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
{3,3xe2x80x3-Dichloro-5xe2x80x2-[8-(4-trifluoromethyl-benzyloxy)-octylcarbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy}-acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-{3-[3-(3-methoxy-propoxy)-propoxy]-propoxy}-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
(3,3xe2x80x3-Dichloro-5xe2x80x2-dicyclohexylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
4-[4,4xe2x80x3-Dimethoxy-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3terphenyl-2xe2x80x2-yloxy]-butyric acid
4-[3,3xe2x80x3-Dichloro-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-butyric acid
[5xe2x80x2-(7-Phenyl-heptylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxymethyl]-phosphonic acid diethyl ester
[5xe2x80x2-(7-Phenyl-heptylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxymethyl]-phosphonic acid
2,2-Dimethyl-3-[5xe2x80x2-(7-phenyl-heptylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2: 3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-propionic acid
4-[5xe2x80x2-(7-Phenyl-heptylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x23xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxymethyl]-benzenesulfonic acid
[[4,4xe2x80x2-Dimethoxy-5xe2x80x2-[4-[[(7-phenylheptyl)amino]carbonyl]phenyl][1,1xe2x80x2:3xe2x80x2,1xe2x80x2-terphenyl]-2xe2x80x2-yl]oxy]acetic acid
[[5xe2x80x2-[4-[[(7-Phenylheptyl)amino]carbonyl]phenyl]-3,3xe2x80x2-bis(trifluoromethyl)[1,1xe2x80x2:3xe2x80x2,1xe2x80x2-terphenyl]-2xe2x80x2-yl]oxy]acetic acid
4-[[[4,4xe2x80x2-Dimethoxy-5xe2x80x2-[4-[[(7-phenylheptyl)amino]carbonyl]phenyl][1,1xe2x80x2:3xe2x80x2,1xe2x80x2-terphenyl]-2xe2x80x2-yloxymethyl]-benzoic acid
4-[5xe2x80x2-(7-Phenyl-heptylcarbamoyl)-3 ,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxymethyl]-benzoic acid
(3-Bromo-3xe2x80x2-chloro-5-dodecylcarbamoyl-4xe2x80x2-fluoro-biphenyl-2-yloxy)acetic acid
[3xe2x80x2-Chloro-4xe2x80x2-fluoro-5-(8-phenyl-octylcarbamoyl)-biphenyl-2-yloxy]acetic acid
(3-Bromo-5-dodecylcarbamoyl-3xe2x80x2-methoxy-biphenyl-2-yloxy)acetic acid
5-Bromo-6-(2-tetrazol-1-yl-ethoxy)-3xe2x80x2-methoxy-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-3xe2x80x2-chloro-6-(2-tetrazol-2-yl-ethoxy)-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-3xe2x80x2-chloro-6-(2-tetrazol-1-yl-ethoxy)-biphenyl-3-carboxylic acid dodecylamide
[3,5,3xe2x80x3,5xe2x80x3-Tetramethyl-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[4,4xe2x80x3-Difluoro-3,3xe2x80x3-dimethyl-5xe2x80x2-(8-phenyloctylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
2xe2x80x2-Hydroxy-3,5,3xe2x80x3,5xe2x80x3-tetramethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (7-phenyl-heptyl)-amide
2xe2x80x2-Hydroxy-3,3xe2x80x3-dimethyl-[1,1:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (7-phenyl-heptyl)-amide
[3,3xe2x80x3-Dimethyl-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
4-[3,3xe2x80x3-Dimethyl-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-butyric acid
[3,5,3xe2x80x3,5xe2x80x3-Tetramethyl-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxymethyl]-phosphonic acid diethyl ester
4-[3,5,3xe2x80x3,5xe2x80x3-Tetramethyl-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-butyric acid
3,3xe2x80x3-Diformyl-2xe2x80x2-methoxymethoxy-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (7-phenyl-heptyl)-amide
3,3xe2x80x3-Diformyl-2xe2x80x2-hydroxy-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (7-phenyl-heptyl)-amide
3,3xe2x80x3,4,4xe2x80x3-Bis-methylenedioxy-5xe2x80x2-(7-phenyl-heptylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
3xe2x80x2-Bromo-2xe2x80x2-hydroxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-biphenyl-3-carboxylic acid 4-chloro-butyl ester
(3xe2x80x3-Chloro-5xe2x80x2-dodecylcarbamoyl-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Dodecylcarbamoyl-4xe2x80x3-methoxy-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Dodecylcarbamoyl-2xe2x80x3-fluoro-4-methoxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-xe2x80x2yloxy)acetic acid
(3-Bromo-5-dodecylcarbamoyl-2xe2x80x2-fluoro-biphenyl-2-yloxy)acetic acid
[4xe2x80x3-Methoxy-5xe2x80x2-(6-phenyl-hexylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[4xe2x80x3-Methoxy-5xe2x80x2-(8-phenyl-octylcarbamoyl)-3-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
(3,5,3xe2x80x3,5xe2x80x3-Tetrachloro-5xe2x80x2-dodecylcarbamoyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
[3,5,3xe2x80x3,5xe2x80x3-Tetrachloro-5xe2x80x2-(8-phenyl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3,5,3xe2x80x3,5xe2x80x3-Tetrachloro-5xe2x80x2-(6-phenyl-hexylcarbamoyl)-[,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
[3,3xe2x80x3-Dichloro-5xe2x80x2-(4-heptyloxy-benzylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
8-[(2xe2x80x2-Carboxymethoxy-3 ,3xe2x80x3-dichloro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carbonyl)-amino]-octanoic acid methyl ester
5-[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-indol-1-yl-octylcarbamoyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-pentanoic acid
4-{2-[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-indol-1-yl-octylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-ethoxy}benzoic acid
4-Methoxybenzoic acid 6-[(2xe2x80x2-carboxymethoxy-3 ,3xe2x80x3-dichloro-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carbonyl)-amino]-hexyl ester
[3,3xe2x80x3-Dichloro-5xe2x80x2-(6-hydroxy-hexylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]acetic acid
2-[3,3xe2x80x3-Dichloro-5xe2x80x2-(8-indol-1-yl-octylcarbamoyl)-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-ethoxy} acetic acid
(5xe2x80x2-Hexyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Nonyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Tridecyl-[1,1;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Decyloxy-[1, 1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Tetradecyloxy-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Trityl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)acetic acid
(5xe2x80x2-Dodecylcarbamoyl-3,3xe2x80x3-bis-trifluoromethyl-{1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(3-Bromo-5-dodecylcarbamoyl-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy)-acetic acid
(5xe2x80x2-(8-Phenyl-octylcarbamoyl-3,3xe2x80x3-bis-trifluoromethyl-{1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy)-acetic acid
(3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy)-acetic acid
4-(3-Bromo-5-dodecylcarbamoyl-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxysulfonyl)-2-hydroxy-benzoic acid
5-Bromo-6-(2-[1,2,3]triazol-2-yl-ethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-6-(2-[1,2,3]triazol-1-yl-ethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-6-(2-tetrazol-2-yl-ethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-6-(2-tetrazol-1-yl-ethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylaamide
Carbamic acid 2-[3-bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy]-ethyl ester
5-Bromo-6-(2-morpholin-4-yl-ethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide
6-(Amino-ethoxy)-5-bromo-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid dodecylamide
5-Bromo-3xe2x80x2-trifluoromethyl-6-(2-ureido-ethoxy)-biphenyl-3-carboxylic acid dodecylamide
[2-(3-Bromo-5-dodecylcarbamoyl-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy)-ethyl]-carbamic acid methyl ester
[5xe2x80x2-(6-Phenyl-hexylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3}terphenyl-2xe2x80x2-yloxy]-acetic acid
[3-Bromo-5-(6-phenyl-hexylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy]-acetic acid
2xe2x80x2-Hydroxy-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x21xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (8-phenyl-octyl)-amide
5-[5xe2x80x2-(8-Phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2yloxy]-pentanoic acid
5-Bromo-6-(2-piperazin-1-yl-ethoxy)-3xe2x80x2trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl)-amide
5-Bromo-6-hydroxy-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl)-amide
4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxysulfonyl]-2-hydroxy-benzoic acid
7-[5xe2x80x2-(8-Phenyl-octylcarbamoyl)-3,3xe2x80x3-bis trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-heptanoic acid
2xe2x80x2-(2-Hydroxy-3,4-dioxo-cyclobut-1-enylamino)-ethoxy]-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (8-phenyl-octyl amide)
2xe2x80x2-[4-(1H-Tetrazol-5-yl)-butoxy-3 ,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (8-phenyl-octyl)-amide
2-Methoxy-4-[5xe2x80x2-(8-phenyl-octylcarbamoyl)-3 ,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2yloxymethyl]-benzoic acid
2-Hydroxy-4-[5xe2x80x2-(8-phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x21xe2x80x3]terphenyl -2xe2x80x2yloxymethyl]-benzoic acid
2-Hydroxy-4-[5xe2x80x2-(8-phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl -2xe2x80x2yloxymethyl]-benzoic acid methyl ester
4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid
2-Hydroxy-4-[5xe2x80x2-(8-phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxysulfonyl]-benzoic acid
4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxymethyl]-2-methoxy-benzoic acid
5-Bromo-6-(1H-tetra-5-ylmethoxy)-3xe2x80x2-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl)-amide
2xe2x80x2-(1H-Tetrazol-5-ylmethoxy)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (8-phenyl-octyl)-amide
4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxymethyl]-2-hydoxy-benzoic acid methyl ester
4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxymethyl]-2-hydroxy-benzoic acid
2xe2x80x2-Amino-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x21xe2x80x3]terphenyl-5xe2x80x2-carboxylic acid (8-phenyl-octyl)-amide
4-[2-Bromo-4-(8-phenyl-octylcarbamoyl)-phenoxysulfonyl]-2-hydroxy-benzoic acid
2-Hydroxy-4-{2-[5xe2x80x2-(8-phenyl-octylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-ethoxy}-benzoic acid
{3-Bromo-5-[methyl-(8-phenyl-octyl)-carbamoyl]-3xe2x80x2-trifluoromethyl-biphenyl-2-yloxy}-acetic acid
{3,3xe2x80x3-Dichloro-4,4xe2x80x3difluoro-5, -[methyl-(8-phenyl-octyl)-carbamoyl]-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3terphenyl-2xe2x80x2yloxy}-acetic acid
[5-Methyl-(8-phenyl-octyl)-carbamoyl]-3 ,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3terphenyl-2xe2x80x2yloxy 1-acetic acid
[5xe2x80x2-(3-Benzyloxy-benzylcarbamoyl)-3,3xe2x80x3-bis-trifluoromethyl-[1,1xe2x80x2:3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxy]-acetic acid
(2-(R)-3-Phenyl-2-[5-(8-phenyl-octylcarbamoyl)-4xe2x80x2-trifluromethyl-biphenyl-2-yloxy]-propionic acid
2-(R)-3-Phenyl-2-[4xe2x80x2-chloro-5-(8-phenyl-octylcarbamoyl)-biphenyl-2-yloxy]-propionic acid
2-(R)-3-Phenyl-2-[4xe2x80x2-fluoro-5-(8-phenyl-octylcarbamoyl)-biphenyl-2-yloxy]-propionic acid
2-(R)-3-Phenyl-2-[4xe2x80x2-methoxy-5-(8-phenyl-octylcarbamoyl)-biphenyl-2-yloxy]-propionic acid
2-(R)-3-Phenyl-2-[5-(8-phenyl-octylcarbamoyl)-4xe2x80x2-trifluoromethoxy-biphenyl-2-yloxy]-propionic acid
or a pharmaceutically acceptable salt thereof.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. These schemes show the preparation of representative compounds of this invention. 
In Scheme 1, the 2-bromophenol (IIa; X=H; Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), available by the procedure of Oberhauser (J. Org. Chem, 1997, 62, 4504) is treated with two or more equivalents of iodine in an aqueous potassium carbonate/THF solution at temperatures between 0xc2x0 C. and room temperature to give the 2-bromo-6-iodophenol (IIb; R=H; X=I; Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN). The 2-bromo-6-iodophenol (IIb; R=H; X=I; Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), the 2-chloro-6-bromophenol (IIc; X=Br; Y=Cl; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), the 2-chloro-6-iodophenol (IId; X=I; Y=Cl; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, xe2x80x94Br), the 2-fluoro-6-bromophenol (IIc; X=Br; Y=F; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), or the 2-fluoro-6-iodophenol (IId; X=I; Y=F; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, xe2x80x94Br) is then subjected to Mitsunobu conditions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27) using ethylene glycol, propane-1,3-diol, or butane-1,4-diol as the nucleophile to give IIIa (R=H; X=I; Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), IIIb (R=H; X=Br; Y=Cl; F; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), or IIIc (R=H; X=I; Y=Cl; F; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, xe2x80x94Br). The other co-reagents necessary to effect the Mitsunobu reaction include one or more molar equivalents of a lower alkyl azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene, or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. This compound is then subjected to Suzuki or Stille coupling conditions using of 1.0 to 1.8 equivalents of a coupling partner to give IVa (Y=Br; R=H; B H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN) and VIa (R=H; B H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN); or IVa (Y=Cl, F; R=H; B H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN). Typical conditions used to carry out the Suzuki reaction include the use of a boronic acid or ester as the coupling partner, a palladium catalyst (2 to 20 mole %) such as Pd(PPh3)4 or [1,1xe2x80x2bis(diphenylphosphino)-ferrocene]dichloro-palladium(11), and a base such as potassium carbonate, barium hydroxide, potassium phosphate, or triethylamine in a suitable solvent such as aqueous dimethoxyethane, THF, acetone, or DMF at temperatures ranging from 25xc2x0 C. to 125xc2x0 C. Typical conditions used to carry out the Stille reaction include the use of an organostannane as the coupling partner, a palladium catalyst (2 to 20 mole %) such as Pd(PPh3)4 or [1,1xe2x80x2bis(diphenylphosphino)ferrocene]-dichloro-palladium(II), and a salt such as potassium fluoride or lithium chloride in a suitable anhydrous solvent such as dimethoxyethane, THF, acetone, or DMF at temperatures ranging from 25xc2x0 C. to 125xc2x0 C.
To obtain the unsymmetrical compound Va (R=H, B H, halogen; D H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN), compound IVa (Y=Br; R=H; B H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN) is subjected again to the above Suzuki or Stille conditions using 1.0 to 1.8 equivalents of a different boronic acid, ester, or organostannane as the coupling partner.
Alternatively, the 2,6-dibromophenol (IIc; X=Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN) or the 2,6-diiodophenol (IId; X=Y=I; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, xe2x80x94Br) can be used as the starting material. Subjection of IIc or IId to Mitsunobu conditions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27) using ethylene glycol, 1,3-propanediol, or 1,4-butanediol as the nucleophile gives 3,5-dihalo derivatives IIIb (R=H; X=Y=Br; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN) or IIIc (R=H; X=Y=I; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, xe2x80x94Br). The other co-reagents necessary to effect the Mitsunobu reaction include one or more molar equivalents of a lower alkyl azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene, or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. This compound is then subjected to Suzuki or Stille coupling conditions using 2.0 equivalents of coupling partner to give VIb (R=H; B H, halogen; C=xe2x80x94CO2Et, xe2x80x94NO2, xe2x80x94CN, Br). Typical conditions used to carry out the Suzuki reaction include the use of a boronic acid or ester as the coupling partner, a palladium catalyst (2 to 20 mole %) such as Pd(PPh3)4 or [1,1xe2x80x2bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base such as potassium carbonate, barium hydroxide, potassium phosphate, or triethylarmine in a suitable solvent such as dimethoxyethane, THF, acetone, or DMF in the presence of a small amount of water at temperatures ranging from 25xc2x0 C. to 125xc2x0 C. Typical conditions used to carry out the Stille reaction include the use of an organostannane as the coupling partner, a palladium catalyst (2 to 20 mole %) such as Pd(PPh3)4 or [1,1xe2x80x2bis(diphenylphosphino)ferrocene]-dichloropalladium(II), and a salt such as potassium fluoride or lithium chloride in a suitable anhydrous solvent such as dimethoxyethane, THF, acetone, or DMF at temperatures ranging from 25xc2x0 C. to 125xc2x0 C. Further Suzuki or Stille reaction of VIb (R=H; B H, halogen; C=Br) would give the derivative VIb (R=H; B H, halogen; C=alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms).
Protection of the primary alcohol in IIIa, IIIb, IIIc, IVa, VIb, or Va can be achieved by reaction with an electrophile such as tBuMe2SiCl, methoxymethyl chloride (MOM-Cl), or methoxyethoxymethyl chloride (MEM-Cl) to give IIIa, IIIb, or IIIc (R=xe2x80x94SiMe2tBu, -MOM, -MEM), IVa (R=xe2x80x94SiMe2tBu, -MOM, -MEM), VIb (R=xe2x80x94SiMe2tBu, -MOM, -MEM), or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM). The other co-reagents necessary to effect the protection include an amine base such as pyridine, triethylamine, diisopropylethylamine, or 4-dimethylaminopyridine in an appropriate anhydrous solvent such as dichloromethane, DMF, or toluene at temperatures ranging from xe2x88x9278xc2x0 C. to 125xc2x0 C. Alternatively, protection of the primary alcohol in IIIa, IIIb, IIIc, IVa, VIb, or Va can be achieved by reaction with a reagent such as 3,4-dihydro-2H-pyran in the presence of a mild acid such as, but not limited to, pyridinium p-toluenesulfonate (PPTS), in a solvent such as dichioromethane to afford the tetrahydropyranyl ethers IIIa, IIIb, or IIIc (R=-THP), IVa (R=-THP), VIb (R=-THP), or Va (R=-THP).
Conversion of IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CN, xe2x80x94CO2Et) to the corresponding aldehydes IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CHO) can be accomplished by reaction with diisobutylaluminum hydride in THF or toluene at xe2x88x9278xc2x0 C. to xe2x88x92100xc2x0 C. These aldehydes can be converted to the corresponding IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=alkyl of 1-18 carbon atoms, arallyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms) through the hydrogenolysis (H2, Pd on C, alcohol solvent, 1 atm, room temperature) of the corresponding IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=CR3xe2x95x90CR3R8) formed by Wittig or Homer-Emmons reaction with 1.0 to 5.0 equivalents of a suitable phosphonium salt or phosphonate ester. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a strong base such as potassium t-butoxide, sodium ethoxide, sodium hydride or n-BuLi in a solvent such as THF, DME, or Et2O at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C.
The aldehydes IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CHO) can further be elaborated by Bayer-Villager oxidation to the formate esters IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94OCHO) followed by saponification to the phenols IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94OR6; R6=H). The Bayer-Villager oxidation is generally performed with 1.0 to 5.0 equivalents of m-chloroperbenzoic acid or other peracid in a solvent such as dichloromethane, chloroform, or benzene at temperatures ranging from 0xc2x0 C. to 125xc2x0 C. Saponification of the formate esters is usually performed in an alcoholic solution of a metal hydroxide, typically sodium hydroxide, at temperatures ranging from 0xc2x0 C. to 125xc2x0 C. The phenols IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H, xe2x80x94SiMetBu, -MOM, -MEM, -THP; C=xe2x80x94OR6; R6=H) can be further elaborated by alkylation with a suitable electrophilic iodide, bromide, tosylate, mesylate, or triflate to give ethers IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94OR6, R6H). The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a base such as cesium carbonate, potassium carbonate, sodium ethoxide, or sodium hydride in a solvent such as THF, DME, DMF, DMSO, or Et2O at temperatures ranging from 0xc2x0 C. to 125xc2x0 C.
The phenols IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94OR6; R6=H) can be further elaborated to the corresponding carboxylic acid esters IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94O2CR6) by reaction with a suitable carboxylic acid halide, carboxylic acid anhydride, or reaction with a carboxylic acid in the presence of an activating agent such as dicyclohexylcarbodiimide or isobutyl chloroformate. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a normucleophilic base such as pyridine, triethylamine, dimethylaminopyridine, or diisopropylethylamine in a solvent such as dichioromethane, toluene, or THF at temperatures ranging from 0xc2x0 C. to 125xc2x0 C.
The phenols IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94OR6; R6=H) can be further elaborated to the corresponding carbamates IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94O2CNR6R7) by reaction with a suitable carbamoyl halide or isocyanate. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a normucleophilic base such as pyridine, triethylamine, dimethylaminopyridine, or diisopropylethylamine in a solvent such as dichloromethane, toluene, or THF at temperatures ranging from 0xc2x0 C. to 125xc2x0 C.
Conversion of carboxylic acid esters IIIa, IIIb, IIIc, IVa, Va, or VIa (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CO2Et) to primary, secondary, or tertiary amides IIIa, IIIb, IIIc, IVa, Va, or VIa (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CONR6R7) can be accomplished by reaction with 2.0 to 5.0 equivalents of lithium amides (derived from reaction of the corresponding amines with BuLi in hexanes in THF or DME at temperatures ranging from xe2x88x9220xc2x0 C. to 25xc2x0 C.) in THF or DME at temperatures ranging from xe2x88x9220xc2x0 C. to 25xc2x0 C. Alternatively, the same conversion could be accomplished by treatment of these esters with 2.0 to 5.0 equivalents of aluminum amides (derived from reaction of AlMe3 with the corresponding amines or their hydrochloride salts in benzene or toluene at temperatures ranging from 25xc2x0 C. to 110xc2x0 C.) in benzene or toluene at temperatures ranging from 25xc2x0 C. to 110xc2x0 C.
Conversion of carboxylic acid esters IIIa, IIIb, IIIc, IVa, Va, or VIa (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CO2Et) to the corresponding benzyl alcohols IIIa, IIIb, IIIc, IVa, Va, or VIa (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CH2OH) can be accomplished by treatment with a suitable reducing agent such as diisobutylaluminum hydride or lithium aluminum hydride in THF or DME at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. The benzyl alcohols can be converted to the corresponding ethers IIIa, IIIb, IIIc, IVa, Va, or VIa (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CH2OR6) by treatment with a suitable base such as sodium hydride followed by reaction with an electrophilic iodide, bromide, mesylate, tosylate, or triflate in a solvent such as THF, DME, or DMF at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C.
Conversion of primary, secondary, or tertiary amides IIIa, IIIb, IIIc, IVa, Va, or VIa (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CONR6R7) to amines IIIa, IIIb, IIIc, IVa, Va, or VIa (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94CH2NR6R7) can be accomplished by reaction with 2.0 to 5.0 equivalents appropriate reducing agent such as diborane or lithium aluminum hydride in THF or DME at temperatures ranging from xe2x88x9220xc2x0 C. to 125xc2x0 C.
Conversion of IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NO2) to the corresponding primary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H, xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NH2) can be accomplished by reaction with an appropriate reducing agent such as iron, sodium dithionite, or H2 using a palladium on carbon catalyst in THF or toluene at xe2x88x9278xc2x0 C. to 100xc2x0 C. These primary anilines can be alkylated in a stepwise fashion to give secondary and tertiary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR6R7; where R6, R7 (together) H). This can be accomplished by sequential reaction of the anilines with appropriate aldehydes in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as EtOH. The primary and secondary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR6R7; R6=H) can be converted to the corresponding carbamates IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR3CO2R6) by reaction with a suitable haloformate. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a normucleophilic base such as pyridine, triethylamine, dimethylamino-pyridine, or diisopropylethylamine in a solvent such as dichloromethane, toluene, or THF at temperatures ranging from 0xc2x0 C. to 125xc2x0 C. The primary and secondary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM,-MEM, -THP; C=xe2x80x94NR6R7; R6=H) can be converted to the corresponding ureas IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR3CONR6R7) by reaction with a suitable carbamoyl halide or isocyanate. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a normucleophilic base such as pyridine, triethylamine, dimethylaminopyridine, or diisopropylethylamine in a solvent such as dichloromethane, toluene, or THF at temperatures ranging from 0xc2x0 C. to 125xc2x0 C. The primary and secondary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR6R7; R6=H) can be converted to the corresponding anilides IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR3COR6) by reaction with a suitable carboxylic acid halide, carboxylic acid anhydride, or reaction with a carboxylic acid in the presence of an activating agent such as dicyclohexylcarbodiimide. The other co-reagents necessary to effect the transformation include 1.0 to 5.0 equivalents of a normucleophilic base such as pyridine, triethylamine, dimethylarinopyridine, or diisopropylethylarmine in a solvent such as dichloromethane, toluene, or THF at temperatures ranging from 0xc2x0 C. to 125xc2x0 C.
The primary and secondary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR6R7; R6=H) can be converted to the corresponding N-aryl-1,2-diaminocyclobutene-3,4-diones IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=) 
by reaction with a suitably substituted 1-ethoxy-2-aminocyclobutene-3,4-dione in an appropriate solvent such as acetonitrile or ethanol at temperatures ranging from room temperature to 80xc2x0 C. Alternatively, the order of reaction can be reversed, where the primary or secondary anilines IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP; C=xe2x80x94NR6R7; R6=H) could be reacted with diethoxysquaric acid in a solvent such as ethanol at temperatures ranging from room temperature to 80xc2x0 C. to afford the 1-amino-2-ethoxycyclobutene-3,4-dione which, in turn, could be treated with an appropriate amine in an appropriate solvent such as acetonitrile or ethanol at temperatures ranging from room temperature to 80xc2x0 C. to give the same N-aryl-1,2-diaminocyclobutene-3,4-diones IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MEM, -THP; C=
The alcohol protecting groups used in the above transformations IIIa, IIIb, IIIc, IVa, VIb, or Va (R=xe2x80x94SiMe2tBu, -MOM, -MEM, -THP) could be removed to give the free alcohol IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H) in a number of ways. The tBuMe2Si group could be removed by treatment with tetrabutylammonium fluoride in a solvent such as THF at temperatures ranging from 0xc2x0 C. to 25xc2x0 C. The MEM group could be removed by treatment with ZnBr2 or TiCl4 in dichloromethane at temperatures ranging from 0xc2x0 C. to 25xc2x0 C. The THP and MOM groups could be removed by treatment with aqueous acetic acid in THF at temperatures ranging from room temperature to 60xc2x0 C.
Further modifications could be performed on the free alcohols of Scheme 1 (IIIa, IIIb, IIIc, IVa, VIb, or Va (R=H)) depicted as the free alcohols VII (R=H) as shown in Scheme 2. Treatment with an oxidizing agent such as tetrapropylammonium perruthenate (TPAP) with 2 or more equivalents of N-methylmorpholine N-oxide (NMMO) or, alternatively, CrO3, in a solvent such as acetonitrile at room temperature gave the corresponding carboxylic acids VIII (R=OH). Treament with TPAP and 1 equivalent of NMMO gave the corresponding aldehydes IX. Conversion fo the free alcohol VII (R=H) to the corresponding mesylate, tosylate, or triflate VII (R=xe2x80x94SO2Me, xe2x80x94SO2PhMe, xe2x80x94SO2CF3) could be accomplished by treatment with mesyl chloride, tosyl chloride, or triflyl chloride in the presence of a normucleophilic base such as pyridine, triethylamine, diisopropylethylanmine, collidine, or 2,6-di-tert-butyl-4-methylpyridine in a solvent such as dichloromethane at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C. Conversion of the free alcohol VII (R=H) to the corresponding bromide or iodide XI (X=Br, I) could be accomplished by treatment with carbon tetrabromnide and triphenylphosphine (X=Br) or with iodine and triphenylphosphine in a solvent such as dichloromethane or THF at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. Conversion of either VII (R=xe2x80x94SO2Me, xe2x80x94SO2PhMe, xe2x80x94SO2CF3) or XII to the nitriles X could be accomplished by reaction with an appropriate alkali metal cyanide such as sodium cyanide in a solvent such as DMF, DMSO, or THF at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. Transformation of the nitrile X to the amide oxime XIII could be accomplished by reaction with hydroxylamine hydrochloride and sodium methoxide in methanol at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. The amide oximes XII could then be converted to the substituted oxadiazoles XIII (R=CH3, H) by reaction with a carboxylic acid chloride, a trialkylorthoester, carboxylic acid anhydride, or a carboxylic acid (in the presence of an activating agent such as dicyclohexylcarbodiimide) in a solvent such as dichloromethane, THF, or acetone at temperatures ranging from xe2x88x9220xc2x0 C. to 60 CC followed by dehydration (Dean-Stark trap, refluxing toluene). Conversion of nitriles X to tetrazoles XIV can be accomplished by reaction with an appropriate metal azide such as sodium azide in the presence of a tertiary amine hydrochloride salt such as triethylammonium chloride in a solvent such as DMF, DMA, or N-methylpyrrolidinone at temperatures ranging from 100xc2x0 C. to 160xc2x0 C. The N-alkylated tetrazoles XV (S=T=U=N, X=CR3 and S=T=X=N, U=CR3), N-alkylated 1,2,3-triazoles XV (S=X=CR3, U=T=N; and S=T=N, X=U=CR3), N-alkylated 1,2,4-triazoles XV (S=X=N, U=T=CR3; and X=T=N, S=U=CR3) and N-alkylated imidazole XV (S=N, X=T=U=CR3) could be made from VII (R=xe2x80x94SO2Me, xe2x80x94SO2PhMe, xe2x80x94SO2CF3) or XI (X=Br, I) by reaction of the anion formed from treatment of tetrazole, 1,2,3-triazole, 1,2,4-triazole, or imidazole with a strong base such as sodium hydride in a solvent such as THF, DME, DMF, or DMSO at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. The amines XVI (R4 H) could be made from VII (R=xe2x80x94SO2Me, xe2x80x94SO2PhMe, xe2x80x94SO2CF3) or XI (X=Br, I) by reaction with 2 or more equivalents of pyrrolidine, piperidine, morpholine, N-methylpiperazine or simple disubstituted amines in a solvent such as dichloromethane, THF, DME, or DMF at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. Alternatively, reaction of VII (R=xe2x80x94SO2Me, xe2x80x94SO2PhMe, xe2x80x94SO2CF3) or XI (X=Br, I) with an alkali metal azide such as sodium azide in a solvent such as DMF, DMSO, or THF at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. would give the azides XI (X=N3). Subsequent treatment of the azides XI (X=N3) with triphenylphosphine in wet THF would give the primary amines XVI (R4=R5=H). Secondary amines XVI (R4=H; R5H) could be made by reaction of the aldehydes IX with primary amines in the presence of a suitable reducing agent such as sodium cyanoborohydride in a solvent such as ethanol or isopropanol at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. The aldehydes IX can be further elaborated by reaction with hydroxylamines or hydrazines in a solvent such as methanol or ethanol at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. to form oximes XVII (X=OR3) and hydrazones XVII (X=NHR3). The alcohols VII (R=H) can be further elaborated by reaction with an appropriate electrophilic alkylating agent such as an alkyl or carboalkoxyalkyl bromide, iodide, mesylate, tosylate, or triflate in the presence of a base such as sodium hydride in a solvent such as THF, DMF, or DME at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. to give ethers VII (R=R3, xe2x80x94CH2CO2R3). The alcohols VII (R=H) can be further elaborated by reaction with an appropriate isocyanate in a solvent such as dichloromethane at temperatures ranging from 0xc2x0 C. to 100xc2x0 C. to give the corresponding carbamates VII (R=CONR4R5). The primary or secondary amines XVI (R4=H) could be converted into the corresponding carbamates XI (X=NR5CO2R3, R3H) by treatment with a suitable haloformate in a solvent such as dichloromethane in the presence of a base such as triethylamine, pyridine, or collidine at temperatures ranging from xe2x88x9220xc2x0 C. to 50xc2x0 C. The carbamates XI (X=NR5CO2R3, R3=p-nitrophenyl) could be converted into the ureas XI (X=NR3CNR4R5) by treatment with a suitable amine in a solvent such as dichloromethane at temperatures ranging from 0xc2x0 C. to 100xc2x0 C. Alternatively, the ureas XI (X=NR3CNR4R5) could be synthesized from the amines XVI (R4=H) by treatment with a suitable isocyanate in a solvent such as dichloromethane at temperatures ranging from 0xc2x0 C. to 100xc2x0 C. 
The carboxylic acids VIII (R=OH) can be converted into the carboxylic acid esters VIII (R=OR3, R3 H) by reaction with a suitable alcohol in the presence of a strong acid catalyst such as sulfuric acid, toluenesulfonic acid, or camphorsulphonic acid in a solvent such as toluene at reflux utilizing a Dean-Stark trap for removal of water. Alternatively, activation of the acid with a reagent such as dicyclohexylcarbodiimide or isobutyl choroformate in the presence of a normucleophilic base such as triethyl amine, pyridine, or diisopropylethylamine in a solvent such as dichloromethane at temperatures ranging from xe2x88x9220xc2x0 C. to 40xc2x0 C. followed by reaction with a suitable alcohol would achieve the same goal. The esters VIII (R=OR3, R3 H, z=1) can be transformed into the alkylated esters XVIII (R=OR3; R3 H; R2 H) by reaction with a suitable base such as LDA or sodium hexamethyldisilazide followed by reaction with a suitable alkylating agent in a solvent such as THF or DME at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C. Saponification of the ester would then lead to the alkylated acids. The conditions to effect this transformation include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. Alternatively, acid conditions may also be employed in which the above mentioned carboxylic acid ester XVIII (R=OR3; R3 H) is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80xc2x0 C.
The esters VIII (R=OR3, R3 H) or XVIII (R=OR3; R3 H; R2 H) can be transformed into the primary amides VIII (R=NH2) or XVIII (R=NH2; R3 H; R2 H) by reacting the ester starting material with ammonia gas dissolved in a lower alcohol solvent such as methanol or ethanol at temperatures ranging from 0xc2x0 C. to 100xc2x0 C.
Alternatively, the carboxylic acids VIII (R=OH) or XVIII (R=OH; R2 H) can be transformed into their carboxylic acid amide analogs VIII (R=NH2, NHOH, NHR3) or XVIII (R=NH2, NHOH, NHR3; R2 H) This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxyl amine and 2-aminopropionitrile. Methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to afford the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0xc2x0 C. to 60xc2x0 C.
Alternatively, the carboxylic acid amide analogs VII (R=NH2) or XVIII (R=NH2) can be converted to their nitrile analogs XI (X=CN) by using reagents that dehydrate the primary carboxamide function to the nitrile function. One set of conditions to effect this transformation include reacting the said primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent such as dioxane at temperatures ranging from 60xc2x0 C. to 120xc2x0 C.
The amines of this invention used as reagents in the conversion to the products of this invention can be either commercially obtained or synthesized by a variety of methods. A carboxylic acid amide can be converted to an amine by reduction with diborane or lithium aluminum hydride in a solvent such as THF, DME, or ether at temperatures ranging from xe2x88x9220xc2x0 C. to room temperature. A halide can be converted to an amine by reaction with the sodium salt of phthalimide in a solvent such as THF or DMF at temperatures ranging from xe2x88x9220xc2x0 C. to room temperature followed by reaction with hydrazine hydrate in a solvent such as methanol at reflux. Alternatively, conversion to the azide by reaction with an alkali metal azide such as sodium azide in a solvent such as DMF or THF at temperatures ranging from xe2x88x9220xc2x0 C. to room temperature followed by reaction with triphenylphosphine in aqueous THF at room temperature gives the amine.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following standard pharmacological test procedure which measures the inhibition of PTPase.
Inhibition of Tri-Phosphorylated Insulin Receptor Dodecaphosphopeptide Dephosphorylation by hPTP1B
This standard pharmacological test procedure assesses the inhibition of recombinant, human protein tyrosine phosphatase (PTP) 1B activity. The substrate for the PTPase assay is a dodecaphosphopeptide corresponding to amino acids 1142-1153 of the insulin receptor (IR) kinase domain that was synthesized to contain phosphotyrosine at residues 1146, 1150 and 1151. The procedure used and results obtained are briefly described below.
Human, recombinant PTP1B (hPTP1B) was prepared as described by Goldstein (see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used was stored in microtubes containing 4000-100001 g/ml protein in 10 mM Tris-HCl, 0.2 mM EDTA, 25 mM NaCl, 50% glycerol and 3 mM DTT.
Measurement of PTPase activity. The malachite green-ammonium molybdate method is used for the nanomolar detection of liberated phosphate by recombinant PTP1B as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979). The assay was adapted for use with a 96-well microtiter platereader. The test procedure uses a dodecaphosphopeptide (TRDIpYETDpYpYRK) custom synthesized by AnaSpec, Inc. (San Jose, Calif.) corresponding to amino acids 1142-1153 of the insulin receptor xcex2-subunit. Phosphotyrosine is incorporated at residues 1146, 1150, and 1151 as indicated. The recombinant hPTP1B is diluted to 1 xcexcg/ml with buffer containing 10 mM Tris-HCl pH 7.4, 10 mM xcex2-mercaptoethanol, and 30% Glycerol yielding an approximate activity of 10000-20000 mmoles inorganic phosphate released/min/mg protein. The diluted enzyme (166.5 xcexcl) is added to 621 xcexcl of reaction buffer containing 81.83 mM HEPES pH 7.4, 1.1 mM xcex2-mercaptoethanol and then preincubated for 5 min at 37xc2x0 C. with 2.5 xcexcl of either test compound or DMSO as control. The dephosphorylation reaction is initiated by adding an aliquot (39.5 xcexcl) of the recombinant hPTP1B:inhibitor preincubation mixture to the appropriate wells of a 96-well microtiter plate containing 10.5 xcexcl of IR triphosphopeptide substrate pre-equilibrated to 37xc2x0 C. A final concentration of 50 mM HEPES, 8.46 mM xcex2-mercaptoethanol and 50 xcexcM IR triphosphopeptide is achieved in the well. After 5 min at 37xc2x0 C., the reaction is terminated by the addition of 200 xcexcL of malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). The stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. Sample blanks are prepared by the addition of 2001 xcexcl MG/AM/Tw to wells containing 10.5 xcexcl of IR triphosphopeptide substrate followed by the addition of 39.5 xcexcl of the recombinant enzyme preincubated with either DMSO or drug. The colored product is allowed to develop at room temperature for 25 min. Sample absorbance is determined at 650 nm using 96-well microtiter platereader (Bio-Tek). Samples and blanks are prepared in quadruplicates.
Caculations: PTPase activity, expressed as nmoles of inorganic phosphate released/min/mg protein, is quantified by extrapolation from a standard curve using known quantities of potassium phosphate. Inhibition of recombinant hPTP1B by test compounds is calculated as a percentage of control (i.e. activity achieved in the presence of DMSO alone). A four parameter, non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. The following results were obtained. Other examples not listed in the table below had PTPase inhibitory activity at concentrations less than 50 xcexcM.
Based in the results obtained in the standard pharmacological test procedure, representative compounds of this invention have been shown to inhibit PTPase activity and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compunds of this invention useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
The following procedures describe the preparation of representative examples of this invention.
3-Bromo-4-hydroxybenzoie Acid Ethyl Ester
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62,4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4.EtO (54% in Et2O, 32.9 mL). The solution was cooled to xe2x88x9215xc2x0 C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above xe2x88x9210xc2x0 C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) xcex4 1.39 (t, J=6.7 Hz, 3H, xe2x80x94CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
3-Bromo-4-hydroxy-5-iodobenzoic Acid Ethyl Ester
To a mixture of 3-bromo-4-hydroxybenzoic acid ethyl ester (69.2 g, 282 mmol) in 2N aqueous potassium carbonate (423 mL) was added sufficient THF to completely dissolve the phenol and make the solution clear (300 to 500 mL). The solution was cooled to 0xc2x0 C. and 12 (158 g, 621 mmol) was added portionwise at such a rate as not to accumulate a large amount of solid 12 on the bottom of the flask. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete in 2 h. Worked up by adding (slowly with caution) solid sodium bisulfite at a rate so excess foarming doesn""t occur. Sodium bisulfite was added until nearly decolorized. The mixture was acidified with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layers combined, washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 90%) as a pale yellow solid. NMR indicated it was suitable for use in the next step without further purification. 1H NMR (300 MHz, CDCl3) xcex4 1.39 (t, J=6.8 Hz, 3H, xe2x80x94CO2CH2CH3), 4.32 (t, J=6.8 Hz, 2H, xe2x80x94CO2CH2CH3), 8.14 (d, 11H, arom), 8.32 (d, 1H, arom).
3-Bromo-4-(2-hydroxyethoxy)-5-iodobenzoic Acid Ethyl Ester
To a mixture of 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 255 mmol) in 1 L of dry THF was added ethylene glycol (63.2 mL, 1.02 mol) and triphenylphosphine (87 g, 322 mmol). The solution was cooled to 0xc2x0 C. and diisopropyl azodicarboxylate (60.2 mL, 306 mmol) was added dropwise with stirring. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete after 3 h. Worked up by removing xcx9cxc2xd of the THF via concentration in vacuo, adding water, and extracting with ethyl acetate several times. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, decanted, and concentrated in vacuo to give a viscous oil which solidified on standing. The major portion of the solid byproducts were removed by stirring with 50% ethyl acetate/hexane. The solid byproduct was filtered off and the liquid was concentrated in vacuo to give a solid which was further purified. Flash chromatography eluting with 5-15% ethyl acetate hexane gave pure 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (65 g, 62%). 1H NMR (300 MHz, CDCl3) xcex4 1.37 (t, J=6.5 Hz, 3H, xe2x80x94CO2CH2CH3), 3.95 (t, J=5 Hz, 2H, xe2x80x94OCH2CH2OH), 4.19 (t, J=5 Hz, 2H, xe2x80x94OCH2CH2OH), 4.32 (t, J=6.5 Hz, 2H, xe2x80x94CO2CH2CH3), 8.18 (d, 1H, arom), 8.37 (d, 1H, arom).